Gamma or lymphotropic herpesviruses are characterized by their ability to cause a life-long latent infection in lymphoid cells. Epstein-Barr virus (EBV) and the Kaposi's Sarcoma Associated Herpesvirus (KSHV/HHV-8) are implicated as causative agents of malignant lymphomas in AIDS patients, in aging individuals, and organ transplant patients. The major psychoactive compound of marijuana delta-9 tetrahydrocannabinol (THC) has been shown to modulate lymphoid cell functions, therefore, we hypothesized that THC is likely to modulate gamma herpesvirus replication. The preliminary data show that THC inhibits lytic but not latent KSHV and EBV DMAreplication in B cell lines. THC also inhibits lytic replication of the murine gamma herpesvirus MHV 68 related to KSHV and EBV. THC inhibits these gamma herpesviruses in micromolar concentrations comparable with known antiviral drugs acyclovir and ganciclovir. However, concentration range of THC that inhibits these gamma herpesviruses is not cytotoxic and does not inhibit replication of herpes simplex type 1, an alpha herpesvirus, indicating selectivity. Based on these observations we hypothesize that THC inhibits gamma herpesviruses through a common mechanism that leads to block of lytic replication. However, THC is also immunosuppressive and may contribute to the development of a more serious gamma herpesvirus infection. The effects of THC on gamma herpesvirus infection will be tested by three aims. The experimental design relies primarily on the murine system that provides a tractable animal model. Aim 1 is planned to identify the gene(s) of MHV 68 inhibited by THC. Aim 2 is designed to evaluate the role of THC receptors (CB1 and CB2) in inhibition of MHV 68. Aim 3 is to examine the effects of THC and the role of CB receptors in vivo on virus replication and latency in mice. This study is significant because THC may modulate gamma herpesvirus latency and reactivation in people using marijuana. Approximately half of the US population will experience EBV infection that lasts for life and there are 4.8 million individuals who regularly use marijuana. We are not aware of any similar work performed in the past so this proposal represents the first study in this important area.